A half century of research in structural chemistry, much of it focusing on the ability of some amino acids to form constant, stable bonds with metal ions, preceded the rapid development in the 1930s and 1940s of a new
range of compounds, initially applied to industrial, and then
increasingly to medical, uses.

First in Germany and then
in the USA, different methods were developed for the production
of chelating substances for specific industrial use, such as
the prevention of calcium in hard water from causing staining
or other problems in textile printing. Citric acid was commonly
used for this purpose until first a compound known as NTA, and
then EDTA (ethylenediamine­tetra­acetic acid), were
developed and patented to do the job more efficiently.

During the Second World War
research was carried out on sodium salts of EDTA in order to
establish whether these would be useful as an antidote to poison
gas. Earlier chelating compounds which had been used in this
role, such as BAL (British anti­Lewisite), had proved effective
when either externally applied or used systemically in neutralizing
the arsenic in poison gas, but had themselves been found to be
severely toxic in other ways.

A compound of sodium citrate
was used in 1941 to chelate lead from the bodies of people poisoned
by this heavy metal and later research established that EDTA
contained a highly effective antidote to heavy metal toxicity
(lead poisoning, for example), since it chelated just as well
with lead as it did with calcium when it was infused into the
bloodstream, and without any side effects.

It was at Georgetown University
that Dr. Martin Rubin (who had studied under Frederick Bersworth,
the major American pioneer researcher into EDTA)
conducted the first research into the biological effects of EDTA
on humans. These studies showed its effects on lowering calcium
levels, although this had not been the objective of the work,
which had focused on discovering its degree, or lack, of toxicity.

According to Dr Rubin, who
was the chief researcher into EDTA's applications in treatment
of humans at that time, a Dr Geschikter was the first to use
an EDTA compound for treatment of a human. This work was also
done at Georgetown University, using the chelating ability of
EDTA to assist in the carrying into a patient of the heavy metal
nickel ­ with which it had been chemically bound ­
in a vain attempt to treat an advanced tumour. There were sadly
no benefits to the patient, but perhaps more importantly from
the viewpoint of the benefits later seen with EDTA usage, there
were no harmful effects either: all of the nickel­EDTA
complex which was put into the patient was found to be excreted
via the urine, unchanged.

It was in the early 1950s
that EDTA was first used in the treatment of lead poisoning,
with pleasantly surprising and often dramatically unexpected
results. Workers in battery factories frequently developed lead
poisoning, as did sailors in the US Navy who painted ships with
lead­based paint. Intravenous infusions of EDTA successfully
dealt with this problem, and indeed to this day the Food and
Drug Administration (FDA) in the USA suggests EDTA chelation
as the ideal method of treating not only lead poisoning but also
as the emergency treatment for hypercalcaemia. It was found that
there was often a marked improvement in the circulatory status
of patients with chronic lead poisoning, who also had atherosclerotic
(atheromatous deposits in the arteries) conditions and who were
being treated by EDTA infusion.

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